Chromosomal copy number variations (CNVs) are common genetic abnormalities in autism spectrum disorder (ASD) and have been identified in approximately 10 percent of individuals with ASD. Currently, there is a knowledge gap in the understanding of the molecular and synaptic mechanisms underlying CNV-associated ASD.
Williams syndrome (WS) is a neurodevelopmental disorder caused by deletions in the 7q11.23 chromosomal region. Individuals with WS show developmental delays, learning disabilities and excessively social behavior. Interestingly, individuals with duplications of this same chromosomal region display a symmetrically opposite phenotype with regard to social behavior. This genomic segment therefore offers a unique opportunity to understand the molecular underpinnings of social behaviors.
Compelling evidence suggests that the 15q11-13 chromosomal region is likely to play a role in autism pathogenesis. Mutations of the UBE3A gene, which is located in this region, cause Angelman syndrome (AS), a neurodevelopmental disorder that has strong phenotypic overlap with autism. UBE3A is an E3 ubiquitin ligase and has been shown to be an important regulator of protein homeostasis and synapse development and plasticity. Separately, there is growing evidence that neuronal autophagy plays a role in supporting proper morphological development and synaptic connectivity refinement.
Recent studies have provided compelling evidence that loss-of-function mutations in the CHD8 gene, which encodes an ATP-dependent chromatin-remodeling factor, are associated with an autism subtype characterized by macrocephaly, specific craniofacial features and gut immobility. The CHD8 protein modifies the structure of chromatin in the cell nucleus, and in vitro studies have suggested that CHD8 might function as a regulator of the developmentally important Wnt and PTEN signaling pathways. Tight control of both of these pathways is critical for normal brain development, and mutations that affect their activity have been strongly associated with autism and brain size. It is therefore important to test whether CHD8 functions as a regulator of these pathways during brain development.
Smith-Magenis syndrome (SMS) is an autism-like neurodevelopmental disorder that causes, among other things, motor and learning disability and obesity. SMS affects 1 in 15,000 to 25,000 people, mostly due to the spontaneous loss of a segment of chromosome 17 in the sperm or the egg that produces the embryo. Loss of one copy of the RAI1 gene, which is located within this chromosomal region, recapitulates most of the symptoms of SMS. Further, having an extra copy of the RAI1-containing segment causes the autism spectrum disorder Potocki-Lupski syndrome (PTLS). While alterations in RAI1 copy number has been linked to a number of neurodevelopmental disorders, the precise function of RAI1 in the brain remains unclear. Liqun Luo and his colleagues at Stanford University aim to understand why changing RAI1 copy number leads to compromised cognitive ability and autism-like symptoms.
Copy number variants (CNVs) are the regions of the human genome that represent significant genetic risk factors for autism and other neurodevelopmental disorders. One such CNV located on chromosome 16, called 16p11.2, confers a high risk for developing autism and intellectual disability when deleted, and autism, schizophrenia, bipolar disorder and intellectual disability when duplicated. Even more intriguingly, 16p11.2 deletions are associated with increased head and brain size in the carriers (macrocephaly), whereas 16p11.2 duplications are associated with the decreased head and brain size (microcephaly). However, the exact mechanism by which this CNV influences brain size is unknown.
A major challenge that researchers face in attempting to understand the molecular mechanisms underlying autism spectrum disorders (ASD) is that thousands of gene mutations have been linked to the disease. Adding to this complexity is that, for many of the implicated genes, different variants have been found in distinct individuals with ASD. Assessing this complexity has proven difficult using traditional low-throughput methods, resulting in a wealth of ASD gene variants without functional phenotyping. To address this issue, Kurt Haas and his colleagues at the University of British Columbia will use a combined approach taking advantage of both high- and low-throughput assays to identify ASD gene variants with strong phenotypes, and to provide information on physiological roles for many poorly characterized ASD-associated genes.
Many of the social and cognitive behavioral impairments associated with autism spectrum disorders (ASDs) are likely caused by changes in early brain development that alter the formation of neural circuits, and in particular, the neural circuitry of the cerebral cortex. Because early brain development is completed long before the onset of any identifiable behavioral changes, most studies of the developmental origins of autism have focused on animal models of genetic syndromes or rare single-gene mutations that lead to ASD-like behaviors. It is not clear how these different syndromes may be related to one another, or how these distinct genetic changes can each lead to similar behavioral outcomes.
Microglia — the brain’s resident immune cells — have many roles in normal brain development that neuroscience is just beginning to ascertain. It has long been known that microglia rapidly transform from a homeostatic to an ‘activated’ state following injury or disease and are recruited to sites of damage. A recent and increasing body of work now indicates that microglia also perform important roles in the normal development of the nervous system. For example, microglia sculpt neuronal circuits by removing under-utilized synapses. Microglia also appear to regulate synaptic maturation and plasticity and can impact behavior.
The hallmarks of autism spectrum disorder (ASD) are deficits in social communication and interaction, but a coherent underlying etiological mechanism for ASD is yet unknown. New sequencing technologies have revealed thousands of unique mutations in individuals with ASD, but not in their unaffected parents. Dubbed de novo mutations, the majority alter only a single amino acid in the protein the gene encodes. Some of these mutations impact protein function; many others do not. Currently there are no good methods to study the functional relevance of this large set of de novo missense mutations, and for this reason they have yet to reveal much about the underlying etiology of ASD.